Recent studies in this laboratory demonstrated that the potent synthetic glucocorticoid, dexamethasone, exerts powerful dose-dependent inhibition of acute morphine-induced secretion of ACTH in the rat. Since pretreatment with a relatively low dose of dexamethasone (100 micrograms/kg) completely blocked the stimulant action of 30 milligrams/Kg morphine on ACTH release, this steroid appears to be an extremely effective antagonist of morphine action on the hypothalamo-pituitary-adrenal system. In view of this finding it is important to determine (1) if dexamethasone counteracts acute and chronic effects of morphine on other functional systems, (2) whether alterations in physiological levels of corticosteroids might influence the rate and degree of development of morphine tolerance and physical dependence, and (3) whether dexamethasone-morphine interaction involves actions of these agents on forebrain structures. Accordingly, three series of investigations are proposed to: (1) study effects of dexamethasone on acute morphine-induced changes in spontaneous activity, respiration, temperature, heart rate, blood pressure and analgesia in rats and toxicity in mice, (2) determine effects of corticosteroid excess (dexamethasone or corticosterone administration) or deprivation (adrenalectomy) on development and maintenance of morphine tolerance and physical dependence produced in rats or mice by daily injection or by subcutaneous implantation or morphine, and (3) explore possible brain sites of dexamethasone antagonism of morphine actions in the rat and study the role of hypothalamic and extrahypothalamic forebrain structures in the naloxone-precipitated morphine abstinence syndrome, including activation of the pituitary-adrenal axis.